If you live in the United States today, there is a good chance that you’ve heard of phytocannabinoids—at least THC and CBD. If you are part of the dietary supplement/natural products industry, it would be near impossible for you not to have heard of phytocannabinoids. Likewise, you almost certainly have heard the myriad claims being made about CBD, some of which are accurate and many of which lack scientific substantiation. During the current craze and fervor over CBD, many people have been unaware of the fact that there are a range of other phytocannabinoids, some of which have excellent research behind them without the regulatory limitation of CBD. One such phytocannabinoid is a terpene known as beta-caryophyllene (β-caryophyllene). Derived from pepper oil, this phytocannabinoid has been shown to be particularly effective in relieving pain and inflammation. That is the focus of this article.
Before jumping directly into the discussion about β-caryophyllene, let’s first gain a basic understanding of the endocannabinoid system (ECS), as well as how β-caryophyllene and other phytocannbinoids work within the ECS.
The ECS is a unique communications system in the brain and body that affects many important functions, including how a person feels, moves and reacts. The ECS is composed of: 1) endocannabinoids which are endogenous neurotransmitter-like compounds that bind to 2) cannabinoid receptors and cannabinoid receptor proteins throughout the nervous system, and 3) enzymes that hydrolyze (i.e. break down) the endocannabinoids. The ECS is involved in regulating a variety of physiological and cognitive processes including fertility,1 pregnancy,2 during pre- and postnatal development,3 appetite, pain-sensation, mood and memory, and in mediating the pharmacological effects of cannabis.4-5 The ECS is also involved in mediating some of the physiological and cognitive effects of voluntary physical exercise in humans and other animals, such as contributing to exercise-induced euphoria as well as modulating locomotor activity and motivational salience for rewards.6-9
Endocannabinoids, Their Receptors and Enzymes
The endocannabinoids of primary importance are N-arachidonylethanolamide (anandamide, AEA) and sn-2-arachidonoylglycerol (2-AG). AEA and 2-AG are broken down by enzymes after they activate the eCS receptors, cannabinoid receptor 1 (CB1) or cannabinoid receptor 2 (CB2). CB1 is most abundantly expressed in the brain, and is also expressed in non-neuronal cells, such as adipocytes and hepatocytes, and in musculoskeletal tissues. CB2 is principally associated with cells governing immune function, although it may also be expressed in the central nervous system.10 The primary endocannabinoid enzymes are fatty acid amide hydrolase and monoacylglycerol lipase. Fatty acid amide hydrolase breaks down AEA, while monoacylglycerol lipase breaks down 2-AG.
As research on the ECS expanded, it became evident that effects of AEA and 2-AG can be enhanced by so-called entourage compounds (i.e., phytocannabinoids) that inhibit their breakdown. These entourage compounds get sacrificed by the enzymes in place of AEA and 2-AG, thereby prolonging the action of these endocannabinoids. These entourage compounds include a range of phytocannabinoids from Cannabis species, as well as related compounds from other plants—such as β-caryophyllene from pepper.11
Terpenes as Phytocannabinoids
Before moving into a discussion of terpenes and the ECS, it is first necessary to answer the question, “Can terpenes also be phytocannabinoids?” After all, they don’t come from the Cannabis genus. In response, consider this analogy: Is vitamin D a steroid hormone or a vitamin? Structurally, it is indeed a steroid hormone. But by virtue of its biochemical function, it is also a vitamin. The fact is that it is both a steroid hormone and a vitamin. The point is that there are many compounds, not specifically related to CBD, which are classified as terpenes, but are also phytocannabinoids. Consider the following written by Gertsch et al.12 in 2010 in the British Journal of Pharmacology:
“Cannabinoids are deﬁned as the terpenophenolic constituents of Cannabis sativa L. and until recently, the phenylterpenoid D9-THC and some of its naturally occurring derivatives were the only plant natural products known to directly interact with cannabinoid receptors. However, in the last few years, several non-cannabinoid plant natural products have been reported to act as cannabinoid receptor ligands. This prompts us to deﬁne ‘phytocannabinoids’ as any plant-derived natural product capable of either directly interacting with cannabinoid receptors or sharing chemical similarity with cannabinoids or both.”
So now let’s consider the β-caryophyllene. A 2008 journal article entitled, “Beta-caryophyllene is a dietary cannabinoid”13 answers the aforementioned question in its title. Likewise, there are multiple articles in peer-reviewed journals that identify β-caryophyllene as a phytocannabinoid.14-24 In conclusion, β-caryophyllene is both a terpene and a phytocannabinoid—just as other terpenes can also be phytocannabinoids.
β-caryophyllene (BCP) is a plant volatile, bicyclic sesquiterpene in a number of common plants, and shown to selectively target the CB2 receptor and to act as a full agonist (i.e., a substance that initiates a physiological response when combined with a receptor).25 It is approved by U.S. Food and Drug Administration (FDA) and European agencies as a food additive, taste enhancer and flavoring agent. To make sure there is no confusion, β-caryophyllene may lawfully be used in dietary supplements, and there is no regulatory challenge in doing so as there is with CBD.
Animal Research With BCP
There is an extensive body of animal research on BCP. This includes research demonstrating that BCP provides anti-inflammatory effects and relief of arthritic symptoms when used alone or when combined with anti-inflammatory medications (methotrexate and/or leflunomide).26 Similarly, mouse research suggests that BCP ameliorates arthritis through a cross-talk between CB2 and PPAR-γ (i.e., a receptor that promotes anti-inflammatory macrophage activation).27 Still other research28 demonstrates that orally administered BCP reduced late phase inflammatory pain responses in the formalin test (i.e., a pain test) in a CB2 receptor-dependent manner.
Speaking of CB2 and PPAR-γ, insulin-resistant and obese male Wistar rats were treated with BCP, and either a CB2 or PPAR-γ antagonist administered before BCP treatment to study the mechanism of BCP actions. BCP alleviated insulin-resistance, oxidative-stress, neuroinflammation and behavioral changes, including improvements in anxiety, depression and memory.29
In a similar study30 investigating the effects of BCP on diet-induced dyslipidemia and vascular inflammation in Wistar rats, results showed that BCP significantly ameliorated all diet-induced alterations in a CB2-dependant manner as it improved glycemic parameters, dyslipidemia and vascular oxidative stress and inflammation. It also downregulated proatherogenic adhesion molecule (i.e., a molecule involved in the production of arthritis and diabetes) and restored vascular nitric oxide expression balance.
Parkinson’s disease (PD) is one of the most common neurodegenerative diseases resulting from the continuous death of dopaminergic neurons in substantia nigra. MPP+ (1-methyl-4-phenylpyridinium) has been reported to be a major neurotoxin causing neurotoxic insults on dopaminergic neurons in humans. Research31 indicates that treatment with BCP suppressed MPP+ which suppressed the release of lactic dehydrogenase (i.e., an indicator of tissue damage) and the generation of reactive oxygen species (ROS). BCP treatment also increased intracellular activity of two powerful antioxidants, glutathione and glutathione peroxidase.
Other benefits of BCP in animal and in-vitro research include:
• An in-vitro study32 demonstrating that BCP was able to induce neuritogenesis (i.e., the formation of neurons) in PC12 cells, a model system for primary neuronal cells that do not express CB2 receptors, suggesting it works by a mechanism independent of cannabinoid receptors.
• A study showing that, given orally, β-Caryophyllene prevented cognitive impairment in Alzheimer’s-affected mice.33
• A study34 that found that adult mice receiving BCP showed amelioration of testing-induced depression and anxiety.
• An in-vitro study35 in which BCP suppressed lipid accumulation in the liver, suggesting potential efficacy in preventing and ameliorating nonalcoholic fatty liver disease and its associated metabolic disorders.
• A mouse study found that oral treatment with BCP reduced induced colitis disease activity colonic macro- and microscopic damage, destructive enzyme activities and levels and expression of inflammatory markers.36
• Another mouse study37 found that injection with BCP was able to reduce neuropathic pain.
Human Research With BCP
Although the body of animal research on BCP is impressive, the real proof of efficacy is the human clinical research. Perhaps the most impressive study38 was published in 2020, examined the effects of BCP on delayed onset muscle soreness (DOMS), which is related to swelling of muscles, tenderness, rigidity, pain, disruption of muscle fiber, alteration in the kinematics of joint, acute tissue damage and reduction in power and strength. However, the researchers had some practical concerns about BCP, due to its poor stability in light, temperature, high volatility and insolubility, which could restrict the medical practices. Consequently, in this study they chose to use liposomal BCP (Rephyll, Aurea Biolabs), which was designed to improve the stability and bioavailability of this phytocannabinoid in powder form through the construction of a nanofiber weaving technology, and characterized by Fourier transform infrared spectroscopy, transmission electron microscopy and differential scanning calorimetry studies. Encapsulation efficiency, loading capacity, and in-vitro release studies revealed that Rephyll can be an effective delivery system for BCP.
In any case, in this human randomized, double-blind, crossover, placebo-controlled trial, subjects were treated with BCP (Rephyll, Aurea Biolabs) (n=20) or placebo (n=20). The results were that the oral consumption of BCP significantly reduced the pain as per the visual assessment score (P=0.003), revealing that BCP effectively reduced DOMS with improved recovery without any side effects due to the bioavailable form of the phytocannabinoid BCP in the liposomal powder formulation.
Another eight-week, randomized, double-blind, placebo-controlled trial investigated the inhibitory effects of BCP on H. pylori and its potential role as an alternative gastrointestinal drug.39 This study categorized subjects into a BCP group (33 patients who received 126 mg/day of BCP) and a placebo group (33 patients who received a placebo preparation). Although neither group experienced H. pylori eradication, results showed that the BCP group showed significant improvement in nausea (p=0.025) and epigastric pain (p=0.018), as well as a significant decrease in serum levels of proinflammatory IL-1β (p=0.038). The authors concluded that BCP improves dyspepsia symptoms and can be considered a useful supplementary treatment for gastrointestinal disease.
Although a terpene, BCP functions as a phytocannabinoid, acting as a full agonist in selectively targeting CB2 receptors. It has been approved by FDA and European agencies as food additive, allowing it to be lawfully be used in dietary supplements. An extensive body of animal research has demonstrated that BCP provides anti-inflammatory and pain-relieving effects as well as other benefits. Human research has demonstrated that liposomal BCP (Rephyll, Aurea Biolabs) is stable, bioavailable and effective at reducing pain associated with DOMS. Additional human research also demonstrated that BCP decreased serum levels of proinflammatory IL-1β and improved dyspepsia symptoms.
1 Klein C, Hill MN, Chang SC, Hillard CJ, Gorzalka BB. Circulating endocannabinoid concentrations and sexual arousal in women. J Sex Med. 2012 Jun;9(6):1588-601.
2 Wang H, Xie H, Dey SK. Endocannabinoid signaling directs periimplantation events. AAPS J. 2006;8(2):E425-32.
3 Fride E. The endocannabinoid-CB(1) receptor system in pre- and postnatal life. Eur J Pharmacol. 2004 Oct 1;500(1-3):289-97.
4 Aizpurua-Olaizola O, Elezgarai I, Rico-Barrio I, Zarandona I, Etxebarria N, Usobiaga A. Targeting the endocannabinoid system: future therapeutic strategies. Drug Discov Today. 2017 Jan;22(1):105-110.
5 Donvito G, Nass SR, Wilkerson JL, Curry ZA, Schurman LD, Kinsey SG, Lichtman AH. The Endogenous Cannabinoid System: A Budding Source of Targets for Treating Inflammatory and Neuropathic Pain. Neuropsychopharmacology. 2018 Jan;43(1):52-79.
6 Tantimonaco M, Ceci R, Sabatini S, Catani MV, Rossi A, Gasperi V, Maccarrone M. Physical activity and the endocannabinoid system: an overview. Cell Mol Life Sci. 2014 Jul;71(14):2681-98.
7 Raichlen DA, Foster AD, Gerdeman GL, Seillier A, Giuffrida A. Wired to run: exercise-induced endocannabinoid signaling in humans and cursorial mammals with implications for the ‘runner’s high’. J Exp Biol. 2012; 215 (Pt 8):1331–1336.
8 Thompson Z, Argueta D, Garland T Jr, DiPatrizio N. Circulating levels of endocannabinoids respond acutely to voluntary exercise, are altered in mice selectively bred for high voluntary wheel running, and differ between the sexes. Physiol Behav. 2017 Mar 1;170:141-150.
9 Kuhn SL, Raichlen DA, Clark AE. What moves us? How mobility and movement are at the center of human evolution. Evol Anthropol. 2016 May 6;25(3):86-97.
10 McPartland JM. The endocannabinoid System: An Osteopathic Perspective. J Am Osteopath Assoc. 2008;108(10):586-600.
11 McPartland JM. The endocannabinoid System: An Osteopathic Perspective. J Am Osteopath Assoc. 2008;108(10):586-600.
12 Gertsch J, Pertwee RG, Di Marzo V. Phytocannabinoids beyond the Cannabis plant – do they exist? Br J Pharmacol. 2010; 160:523-529.
13 Gertsch J, Leonti M, Raduner S, et al. Beta-caryophyllene is a dietary cannabinoid. PNAS. 2008;105:9099-9104.
14 Klauke AL, Racz I, Pradier B, Markert A, Zimmer AM, Gertsch J, Zimmer A. The cannabinoid CB2 receptor-selective phytocannabinoid beta-caryophyllene exerts analgesic effects in mouse models of inflammatory and neuropathic pain. Eur Neuropsychopharmacol. 2014 Apr;24(4):608-20.
15 Youssef DA, El-Fayoumi HM2, Mahmoud MF. Beta-caryophyllene protects against diet-induced dyslipidemia and vascular inflammation in rats: Involvement of CB2 and PPAR-γ receptors. Chem Biol Interact. 2019 Jan 5;297:16-24.
16 Santos PS, Oliveira TC, Junior LMR, Figueiras A, Nunes LCC. β-caryophyllene Delivery Systems: Enhancing the Oral Pharmacokinetic and Stability. Curr Pharm Des. 2018;24:1-14.
17 Wang G, Ma W, Du J. β-Caryophyllene (BCP) ameliorates MPP+ induced cytotoxicity. Biomed Pharmacother. 2018 Jul;103:1086-1091.
18 Meza A, Lehmann C. Betacaryophyllene – A phytocannabinoid as potential therapeutic modality for human sepsis? Med Hypotheses. 2018 Jan;110:68-70.
19 Oliveira GLDS, Machado KC, Machado KC, da Silva APDSCL, Feitosa CM, de Castro Almeida FR. Non-clinical toxicity of β-caryophyllene, a dietary cannabinoid: Absence of adverse effects in female Swiss mice. Regul Toxicol Pharmacol. 2018 Feb;92:338-346.
20 Alberti TB, Barbosa WL, Vieira JL, Raposo NR, Dutra RC. (-)-β-Caryophyllene, a CB2 Receptor-Selective Phytocannabinoid, Suppresses Motor Paralysis and Neuroinflammation in a Murine Model of Multiple Sclerosis. Int J Mol Sci. 2017 Apr 1;18(4). pii: E691.
21 Santos NA, Martins NM, Sisti FM, Fernandes LS, Ferreira RS, de Freitas O, Santos AC. The cannabinoid beta-caryophyllene (BCP) induces neuritogenesis in PC12 cells by a cannabinoid-receptor-independent mechanism. Chem Biol Interact. 2017 Jan 5;261:86-95.
22 Kamikubo R, Kai K, Tsuji-Naito K, Akagawa M. β-Caryophyllene attenuates palmitate-induced lipid accumulation through AMPK signaling by activating CB2 receptor in human HepG2 hepatocytes. Mol Nutr Food Res. 2016 Oct;60(10):2228-2242.
23 Sharma C, Al Kaabi JM, Nurulain SM, et al. Polypharmacological Properties and Therapeutic Potential of β-Caryophyllene: A Dietary Phytocannabinoid of Pharmaceutical Promise. Curr Pharm Des. 2016;22:1-28.
24 Ojha S, Javed H, Azimullah S, Haque ME. β-Caryophyllene, a phytocannabinoid attenuates oxidative stress, neuroinflammation, glial activation, and salvages dopaminergic neurons in a rat model of Parkinson disease. Mol Cell Biochem. 2016 Jul;418(1-2):59-70.
25 Gertsch J, Pertwee RG, Di Marzo V. Phytocannabinoids beyond the Cannabis plant – do they exist? Br J Pharmacol. 2010; 160:523-529.
26 El-Sheikh SMA, Abd El-Alim AEF, Galal AAA, El-Sayed RG, El-Naseery NI. Anti-arthritic effect of β-caryophyllene and its ameliorative role on methotrexate and/or leflunomide-induced side effects in arthritic rats. Life Sci. 2019 Aug 10;233:116750.
27 Irrera N, D’Ascola A, Pallio G, Bitto A, Mazzon E, Mannino F, Squadrito V, Arcoraci V, Minutoli L, Campo GM, Avenoso A, Bongiorno EB, Vaccaro M, Squadrito F, Altavilla D. β-Caryophyllene Mitigates Collagen Antibody Induced Arthritis (CAIA) in Mice Through a Cross-Talk between CB2 and PPAR-γ Receptors. Biomolecules. 2019 Jul 31;9(8). pii: E326.
28 Klauke AL, Racz I, Pradier B, Markert A, Zimmer AM, Gertsch J, Zimmer A. The cannabinoid CB2 receptor-selective phytocannabinoid beta-caryophyllene exerts analgesic effects in mouse models of inflammatory and neuropathic pain. Eur Neuropsychopharmacol. 2014 Apr;24(4):608-20.
29 Youssef DA, El-Fayoumi HM, Mahmoud MF. Beta-caryophyllene alleviates diet-induced neurobehavioral changes in rats: The role of CB2 and PPAR-γ receptors. Biomed Pharmacother. 2019 Feb;110:145-154.
30 Youssef DA, El-Fayoumi HM, Mahmoud MF. Beta-caryophyllene protects against diet-induced dyslipidemia and vascular inflammation in rats: Involvement of CB2 and PPAR-γ receptors. Chem Biol Interact. 2019 Jan 5;297:16-24.
31 Wang G, Ma W, Du J. β-Caryophyllene (BCP) ameliorates MPP+ induced cytotoxicity. Biomed Pharmacother. 2018 Jul;103:1086-1091.
32 Santos NA, Martins NM, Sisti FM, Fernandes LS, Ferreira RS, de Freitas O, Santos AC. The cannabinoid beta-caryophyllene (BCP) induces neuritogenesis in PC12 cells by a cannabinoid-receptor-independent mechanism. Chem Biol Interact. 2017 Jan 5;261:86-95.
33 Cheng Y, Dong Z, Liu S. β-Caryophyllene ameliorates the Alzheimer-like phenotype in APP/PS1 Mice through CB2 receptor activation and the PPARγ pathway. Pharmacology. 2014;94(1-2):1-12.
34 Bahi A, Al Mansouri S, Al Memari E, et al. β-Caryophyllene, a CB2 receptor agonist produces multiple behavioral changes relevant to anxiety and depression in mice. Physiol Behav. 2014 Aug;135:119-24.
35 Kamikubo R, Kai K, Tsuji-Naito K, Akagawa M. β-Caryophyllene attenuates palmitate-induced lipid accumulation through AMPK signaling by activating CB2 receptor in human HepG2 hepatocytes. Mol Nutr Food Res. 2016 Oct;60(10):2228-2242.
36 Bento AF, Marcon R, Dutra RC, et al. β-Caryophyllene inhibits dextran sulfate sodium-induced colitis in mice through CB2 receptor activation and PPARγ pathway. Am J Pathol. 2011 Mar;178(3):1153-66.
37 Kuwahata H, Katsuyama S, Komatsu T, et al. Local Peripheral Effects of β-Caryophyllene through CB2 Receptors in Neuropathic Pain in Mice. Pharm. Pharmacol. 2012; 3:397-403
38 Amalraj A, Jacob J, Varma K, Gopi S. Preparation and Characterization of Liposomal β-Caryophyllene (Rephyll) by Nanofiber Weaving Technology and Its Effects on Delayed Onset Muscle Soreness (DOMS) in Humans: A Randomized, Double-Blinded, Crossover-Designed, and Placebo-Controlled Study. ACS Omega. 2020 Sep 8;5(37):24045-24056.
39 Shim HI, Song DJ, Shin CM, et al. [Inhibitory Effects of β-caryophyllene on Helicobacter pylori Infection: A Randomized Double-blind, Placebo-controlled Study] [Article in Korean] Korean J Gastroenterol. 2019 Oct 25;74(4):199-204.
Gene Bruno, MS, MHS, the dean of academics for Huntington College of Health Sciences, is a nutritionist, herbalist, writer and educator. For more than 30 years he has educated and trained natural product retailers and health care professionals, has researched and formulated natural products for dozens of dietary supplement companies, and has written articles on nutrition, herbal medicine, nutraceuticals and integrative health issues for trade, consumer magazines and peer-reviewed publications. He can be reached at email@example.com.